Bioabsorbable device having encapsulated additives for accelerating degradation

ABSTRACT

A medical device has a structure made of one biodegradable and/or bioabsorbable material. A degradation additive is encapsulated by another biodegradable and/or bioabsorbable material forming a nanoparticle or microparticle. The nanoparticle or microparticle is together with the one biodegradable and/or bioabsorbable material of the structure. The other biodegradable and/or bioabsorbable material of the nanoparticle or microparticle has a degradation rate that is faster than a degradation rate of the one biodegradable and/or bioabsorbable material. The structure experiences a period of accelerated degradation upon release of the degradation additive from the nanoparticle or microparticle.

FIELD AND BACKGROUND OF THE INVENTION

The present invention relates, in general, to implantable medicaldevices, and, in particular, to new and useful bioabsorbable medicaldevices that are capable of achieving a desired mass loss throughaccelerated degradation after the medical device has achieved itsdesired functional effect or achieved the end of its functional purposeor useful life.

It is widely accepted that polymers have found very relevant andpractical uses in the medical field. Thus, the very instability of thesepolymers, which lead to biodegradation, has proven to be immenselyimportant in medical applications over the last number of decades.

For example, polymers prepared from glycolic acid and lactic acid havefound a multitude of uses in the medical industry, beginning with thebiodegradable sutures first approved in the 1960's. Since that time,diverse products based on lactic and glycolic acid—and on othermaterials, including poly (dioxanone), poly (trimethylene carbonate)copolymers, and poly (ε-caprolactone) homopolymers and copolymers—havebeen accepted for use as medical devices. In addition to these approveddevices, a great deal of research continues on polyanhydrides,polyorthoesters, polyphosphazenes, and other biodegradable polymers.

There are a number of reasons as to why a medical practitioner desires amedical device made of a material that degrades. And, the most basicreason begins with the physician's simple desire to have a device thatcan be used as an implant and will not require a second surgicalintervention for removal. Besides eliminating the need for a secondsurgery, the biodegradation may offer other advantages. For example, afractured bone that has been fixated with a rigid, nonbiodegradablestainless steel implant has a tendency for refracture upon removal ofthe implant. Because the stress is borne by the rigid stainless steel,the bone has not been able to carry sufficient load during the healingprocess.

However, an implant prepared from biodegradable polymer can beengineered to degrade at a rate that will slowly transfer load to thehealing bone. Another exciting use for which biodegradable polymersoffer tremendous potential is as the basis for drug delivery, either asa drug delivery system alone or in conjunction to functioning as amedical device.

Bioabsorbable implants are typically made from polymeric materials suchas lactone-based polyesters. These bulk eroding materials breakdown overtime due to chemical hydrolysis to produce water-soluble, low molecularweight fragments. These fragments are then attacked by enzymes toproduce lower molecular weight metabolites.

To date, there have been no known bioabsorbable medical devices that arecapable of achieving a desired mass loss through accelerated degradationafter the medical device has achieved its desired functional effect orachieved the end of its functional purpose or useful life.

SUMMARY OF THE INVENTION

The present invention relates to medical devices that are placed orimplanted in the body including medical devices that are placed invessels such as an artery or a vein or ducts or organs such as theheart. Particularly, the present invention is a medical device that iseither made of composite structures comprising biodegradable and/orbioabsorbable material including blends, coatings or layers ofbiodegradable and/or bioabsorbable material for achieving a desired massloss through accelerated degradation after the medical device hasachieved its desired functional effect or achieved the end of itsfunctional purpose or useful life.

Additionally, the present invention is a medical device that is eithermade of biodegradable and/or bioabsorbable material including blends,coatings or layers of biodegradable and/or bioabsorbable material andhaving encapsulated degradation additives conducive for acceleratingdegradation of the structures or components of the medical device forachieving a desired mass loss through accelerated degradation after themedical device has achieved its desired functional effect or achievedthe end of its functional purpose or useful life. In some embodiments,the medical device in accordance with the present invention includes atherapeutic agent released from the medical device as well as otheradditives such as radiopaque agents and buffering agents.

The present invention is directed to a medical device having a structuremade of a first biodegradable and/or bioabsorbable material and a secondbiodegradable and/or bioabsorbable material. The first biodegradableand/or bioabsorbable material has a degradation rate that is faster thana degradation rate of the second biodegradable and/or bioabsorbablematerial. And, the structure experiences a period of accelerateddegradation upon exposure of the first biodegradable and/orbioabsorbable material.

The present invention is also directed to a medical device having astructure made of one biodegradable and/or bioabsorbable material. Adegradation additive is encapsulated by another biodegradable and/orbioabsorbable material forming a nanoparticle or microparticle. Thenanoparticle or microparticle is together with the one biodegradableand/or bioabsorbable material of the structure. The other biodegradableand/or bioabsorbable material of the nanoparticle or microparticle has adegradation rate that is faster than a degradation rate of the onebiodegradable and/or bioabsorbable material. The structure experiences aperiod of accelerated degradation upon release of the degradationadditive from the nanoparticle or microparticle.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. The invention itself, however, both as toorganization and methods of operation, together with further objects andadvantages thereof, may be understood by reference to the followingdescription, taken in conjunction with the accompanying drawings inwhich:

FIG. 1 is a schematic illustration of a medical device having acomposite structure of a first biodegradable and/or bioabsorbablematerial that degrades at a first degradation rate and a secondbiodegradable and/or bioabsorbable material layered or coated over thefirst biodegradable and/or bioabsorbable material, wherein the firstdegradation rate of the first biodegradable and/or bioabsorbablematerial is faster than the second degradation rate second biodegradableand/or bioabsorbable material in accordance with the present invention;

FIG. 2 is a schematic illustration of a portion of structure of themedical device of FIG. 1 in accordance with the present invention;

FIG. 3 is a schematic illustration of a portion of structure of themedical device of FIG. 1 wherein a drug is incorporated therein forrelease in accordance with the present invention;

FIG. 4 is a schematic illustration of a portion of structure of themedical device of FIG. 1 wherein an additive such as a degradationadditive, buffering agent, radiopaque agent or the like is incorporatedtherein for release in accordance with the present invention;

FIG. 5 is a schematic illustration of a portion of structure of themedical device of FIG. 1 wherein both an additive such as a degradationadditive, buffering agent, radiopaque agent or the like and a drug areincorporated therein for release in accordance with the presentinvention;

FIG. 6 is a schematic illustration of a medical device having acomposite structure of a first biodegradable and/or bioabsorbablematerial and an encapsulated degradation additive, shown as across-sectional slice taken from a sphere, in accordance with thepresent invention;

FIG. 7 is a schematic illustration of a portion of structure of themedical device of FIG. 6 in accordance with the present invention;

FIG. 8 is a schematic illustration of a portion of structure of themedical device of FIG. 6 wherein a drug is incorporated therein forrelease in accordance with the present invention;

FIG. 9 is a schematic illustration of a portion of structure of themedical device of FIG. 6 wherein both a degradation additive and a drugare encapsulated therein, shown as a cross-sectional slice taken from asphere, for release in accordance with the present invention; and

FIG. 10 is a graph schematically illustrating the different transitionphases of degradation of the physical structure as a function of timefor implantable biodegradable and/or bioabsorbable medical devicesincluding comparisons of the current mass loss curve associated withknown bioabsorbable medical implants versus the desired mass loss curvefor an implantable biodegradable and/or bioabsorbable medical deviceassociated with the present invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention relates to medical devices that are placed orimplanted in the body including medical devices that are placed invessels such as an artery or a vein or ducts or organs such as theheart. Particularly, the present invention is a medical device that iseither made of composite structures comprising biodegradable and/orbioabsorbable material including blends, coatings or layers ofbiodegradable and/or bioabsorbable material for achieving a desired massloss through accelerated degradation after the medical device hasachieved its desired functional effect or achieved the end of itsfunctional purpose or useful life.

Additionally, the present invention is a medical device that is eithermade of biodegradable and/or bioabsorbable material including blends,coatings or layers of biodegradable and/or bioabsorbable material andhaving encapsulated degradation additives conducive for acceleratingdegradation of the structures or components of the medical device forachieving a desired mass loss through accelerated degradation after themedical device has achieved its desired functional effect or achievedthe end of its functional purpose or useful life. In some embodiments,the medical device in accordance with the present invention includes atherapeutic agent released from the medical device as well as otheradditives such as radiopaque agents and buffering agents.

As used herein, the terms “biodegradable”, “biodegradation”,“degradable”, “degradation”, “degraded”, “bioerodible”, “erodible” or“erosion ” are used interchangeably and are defined as the breaking downor the susceptibility of a material or component to break down or bebroken into products, byproducts, components or subcomponents over timesuch as days, weeks, months or years.

As used herein, the terms “bioabsorbable”, “absorbable”, “resorbable”and “bioresorbable” are used interchangeably and are defined as thebiologic elimination of any of the products of degradation by metabolismand/or excretion.

As used herein, the terms “degradation additive”, “selected enzyme”,“high pH material”, are used interchangeably and defined as anymaterial, agent, compound or substance that accelerates degradation ofthe structure, components or material of the medical device.

As used herein, the terms “buffering agent”, “buffering compound”,“buffer”, “neutralizing agent”, “neutralizing compound”, “neutralizationagent”, or “neutralization compound” are used interchangeably anddefined as any material, agent, compound or substance that limits ormoderates the rate of change of the pH of a medical device or the localor near environment of the medical devices upon exposure to acid orbase.

As used herein, the term “biodegradable material”, “biodegradablepolymer”, “bioabsorbable material”, “bioabsorbable polymer”,“biomaterial”, “biodegradable and/or bioabsorbable material” or“biodegradable and/or bioabsorbable polymer” are used interchangeablyand are defined as any polymer material that is biodegradable orbioabsorbable in the body.

As used herein, the term “composite”, “composite biodegradablematerial”, “composite biodegradable polymer”, “composite bioabsorbablematerial”, “composite bioabsorbable polymer”, “composite biomaterial”,“composite biodegradable and/or bioabsorbable material” or “compositebiodegradable and/or bioabsorbable polymer” are used interchangeably andare defined as two or more polymer materials that are used incombination and are biodegradable or bioabsorbable in the body.

As used herein, the terms “agent”, “therapeutic agent”, “active agent”,“drug”, “active drug”, and “pharmaceutical agent” are usedinterchangeably herein and define an agent, drug, compound, compositionof matter or mixture thereof which provides some therapeutic, oftenbeneficial, effect. This includes pesticides, herbicides, germicides,biocides, algicides, rodenticides, fungicides, insecticides,antioxidants, plant growth promoters, plant growth inhibitors,preservatives, antipreservatives, disinfectants, sterilization agents,catalysts, chemical reactants, fermentation agents, foods, foodsupplements, nutrients, cosmetics, drugs, vitamins, sex sterilants,fertility inhibitors, fertility promoters, microorganism attenuators andother agents that benefit the environment of use. As used herein, theterms further include any physiologically or pharmacologically activesubstance that produces a localized or systemic effect or effects inanimals, including warm blooded mammals, humans and primates; avians;domestic household or farm animals such as cats, dogs, sheep, goats,cattle, horses and pigs; laboratory animals such as mice, rats andguinea pigs; fish; reptiles; zoo and wild animals; and the like. Theactive drug that can be delivered includes inorganic and organiccompounds, including, without limitation, drugs which act on theperipheral nerves, adrenergic receptors, cholinergic receptors, theskeletal muscles, the cardiovascular system, smooth muscles, the bloodcirculatory system, synoptic sites, neuroeffector junctional sites,endocrine and hormone systems, the immunological system, thereproductive system, the skeletal system, autacoid systems, thealimentary and excretory systems, the histamine system and the centralnervous system. Suitable agents may be selected from, for example,proteins, enzymes, hormones, polynucleotides, nucleoproteins,polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids,hypnotics and sedatives, psychic energizers, tranquilizers,anticonvulsants, muscle relaxants, antiparkinson agents, analgesics,anti-inflammatories, local anesthetics, muscle contractants, bloodpressure medications and cholesterol lowering agents including statins,antimicrobials, antimalarials, hormonal agents including contraceptives,sympathomimetics, polypeptides and proteins capable of elicitingphysiological effects, diuretics, lipid regulating agents,antiandrogenic agents, antiparasitics, neoplastics, antineoplastics,hypoglycemics, nutritional agents and supplements, growth supplements,fats, ophthalmics, antienteritis agents, electrolytes and diagnosticagents.

Examples of the therapeutic agents or drugs 99 useful in this inventioninclude prochlorperazine edisylate, ferrous sulfate, aminocaproic acid,mecaxylamine hydrochloride, procainamide hydrochloride, amphetaminesulfate, methamphetamine hydrochloride, benzphetamine hydrochloride,isoproteronol sulfate, phenmetrazine hydrochloride, bethanecholchloride, methacholine chloride, pilocarpine hydrochloride, atropinesulfate, scopolamine bromide, isopropamide iodide, tridihexethylchloride, phenformin hydrochloride, methylphenidate hydrochloride,theophylline cholinate, cephalexin hydrochloride, diphenidol, meclizinehydrochloride, prochlorperazine maleate, phenoxybenzamine,thiethylperazine maleate, anisindione, diphenadione, erythrityltetranitrate, digoxin, isoflurophate, acetazolamide, methazolamide,bendroflumethiazide, chlorpropamide, tolazamide, chlormadinone acetate,phenaglycodol, allopurinol, aluminum aspirin, methotrexate, acetylsulfisoxazole, hydrocortisone, hydrocorticosterone acetate, cortisoneacetate, dexamethasone and its derivatives such as betamethasone,triamcinolone, methyltestosterone, 17-.beta.-estradiol, ethinylestradiol, ethinyl estradiol 3-methyl ether, prednisolone,17-.beta.-hydroxyprogesterone acetate, 19-nor-progesterone, norgestrel,norethindrone, norethisterone, norethiederone, progesterone,norgesterone, norethynodrel, indomethacin, naproxen, fenoprofen,sulindac, indoprofen, nitroglycerin, isosorbide dinitrate, propranolol,timolol, atenolol, alprenolol, cimetidine, clonidine, imipramine,levodopa, chlorpromazine, methyldopa, dihydroxyphenylalanine,theophylline, calcium gluconate, ketoprofen, ibuprofen, atorvastatin,simvastatin, pravastatin, fluvastatin, lovastatin, cephalexin,erythromycin, haloperidol, zomepirac, ferrous lactate, vincamine,phenoxybenzamine, diltiazem, milrinone, captropril, mandol, quanbenz,hydrochlorothiazide, ranitidine, flurbiprofen, fenbufen, fluprofen,tolmetin, alclofenac, mefenamic, flufenamic, difuninal, nimodipine,nitrendipine, nisoldipine, nicardipine, felodipine, lidoflazine,tiapamil, gallopamil, amlodipine, mioflazine, lisinopril, enalapril,captopril, ramipril, enalaprilat, famotidine, nizatidine, sucralfate,etintidine, tetratolol, minoxidil, chlordiazepoxide, diazepam,amitriptylin, and imipramine. Further examples are proteins and peptideswhich include, but are not limited to, insulin, colchicine, glucagon,thyroid stimulating hormone, parathyroid and pituitary hormones,calcitonin, renin, prolactin, corticotrophin, thyrotropic hormone,follicle stimulating hormone, chorionic gonadotropin, gonadotropinreleasing hormone, bovine somatotropin, porcine somatropin, oxytocin,vasopressin, prolactin, somatostatin, lypressin, pancreozymin,luteinizing hormone, LHRH, interferons, interleukins, growth hormonessuch as human growth hormone, bovine growth hormone and porcine growthhormone, fertility inhibitors such as the prostaglandins, fertilitypromoters, growth factors, and human pancreas hormone releasing factor.

Moreover, drugs or pharmaceutical agents 99 useful for the medicaldevice 50 include: antiproliferative/antimitotic agents includingnatural products such as vinca alkaloids (i.e. vinblastine, vincristine,and vinorelbine), paclitaxel, epidipodophyllotoxins (i.e. etoposide,teniposide), antibiotics (dactinomycin (actinomycin D) daunorubicin,doxorubicin and idarubicin), anthracyclines, mitoxantrone, bleomycins,plicamycin (mithramycin) and mitomycin, enzymes (L-asparaginase whichsystemically metabolizes L-asparagine and deprives cells which do nothave the capacity to synthesize their own asparagine); antiplateletagents such as G(GP)II_(b)III_(a) inhibitors and vitronectin receptorantagonists; antiproliferative/antimitotic alkylating agents such asnitrogen mustards (mechlorethamine, cyclophosphamide and analogs,melphalan, chlorambucil), ethylenimines and methylmelamines(hexamethylmelamine and thiotepa), alkyl sulfonates-busulfan,nirtosoureas (carmustine (BCNU) and analogs, streptozocin),trazenes—dacarbazinine (DTIC); antiproliferative/antimitoticantimetabolites such as folic acid analogs (methotrexate), pyrimidineanalogs (fluorouracil, floxuridine, and cytarabine), purine analogs andrelated inhibitors (mercaptopurine, thioguanine, pentostatin and2-chlorodeoxyadenosine {cladribine }); platinum coordination complexes(cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane,aminoglutethimide; hormones (i.e. estrogen); anticoagulants (heparin,synthetic heparin salts and other inhibitors of thrombin); fibrinolyticagents (such as tissue plasminogen activator, streptokinase andurokinase), aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab;antimigratory; antisecretory (breveldin); antiinflammatory: such asadrenocortical steroids (cortisol, cortisone, fludrocortisone,prednisone, prednisolone, 6α-methylprednisolone, triamcinolone,betamethasone, and dexamethasone), non-steroidal agents (salicylic acidderivatives i.e. aspirin; para-aminophenol derivatives i.e.acetominophen; indole and indene acetic acids (indomethacin, sulindac,and etodalac), heteroaryl acetic acids (tolmetin, diclofenac, andketorolac), arylpropionic acids (ibuprofen and derivatives), anthranilicacids (mefenamic acid, and meclofenamic acid), enolic acids (piroxicam,tenoxicam, phenylbutazone, and oxyphenthatrazone), nabumetone, goldcompounds (auranofin, aurothioglucose, gold sodium thiomalate);immunosuppressives: (cyclosporine, tacrolimus (FK-506), sirolimusanalogs (rapamycin), azathioprine, mycophenolate mofetil); angiogenicagents: vascular endothelial growth factor (VEGF), fibroblast growthfactor (FGF) platelet derived growth factor (PDGF), erythropoetin,;angiotensin receptor blocker; nitric oxide donors; anti-senseoligionucleotides and combinations thereof, cell cycle inhibitors, mTORinhibitors, growth factor signal transduction kinase inhibitors,chemical compound, biological molecule, nucleic acids such as DNA andRNA, amino acids, peptide, protein or combinations thereof

It is to be understood that the use of the term “agent”, “therapeuticagent”, “active agent”, “drug”, “active drug”, and “pharmaceuticalagent” includes all derivatives, analogs and salts thereof and in no wayexcludes the use of two or more such agents, therapeutic agents, activeagents, drugs, active drugs, or pharmaceutical agents.

The present invention as best illustrated in FIGS. 1-9 is a medicaldevice 50 such as a medical implant constructed of biodegradable and/orbioabsorbable polymers that are either natural or synthetic. In general,synthetic polymers offer greater advantages than natural materials inthat they can be tailored to give a wider range of properties and morepredictable lot-to-lot uniformity than can materials from naturalsources. Synthetic polymers also represent a more reliable source of rawmaterials, one free from concerns of immunogenicity.

The general criteria for selecting a polymer for use as a biomaterial (abiodegradable and/or bioabsorbable material) is to match the mechanicalproperties and the time of degradation to the needs of the application.The ideal polymer for a particular application is configured so that it:(i) has mechanical properties that match the application, remainingsufficiently strong until the surrounding tissue has healed, (ii) doesnot invoke an inflammatory or toxic response, (iii) is metabolized inthe body after fulfilling its purpose, leaving no trace, (iv) is easilyprocessable into the final product form, (v) demonstrates acceptableshelf life, and (vi) is easily sterilized.

The factors affecting the mechanical performance of biodegradablepolymers are those that are well known to the polymer scientist, andinclude monomer selection, initiator selection, process conditions, andthe presence of additives. These factors in turn influence the polymer'shydrophilicity, crystallinity, melt and glass-transition temperatures,molecular weight, molecular-weight distribution, end groups, sequencedistribution (random versus blocky), and presence of residual monomer oradditives.

In addition, the polymer scientist working with biodegradable materialsmust evaluate each of these variables for its effect on biodegradation.Biodegradation has been accomplished by synthesizing polymers that havehydrolytically unstable linkages in the backbone. The most commonchemical functional groups with this characteristic are esters,anhydrides, orthoesters, and amides.

Preferably, the medical device 50 has a structure, components orfeatures at least one biodegradable and/or bioabsorbable polymer thathas crystalline, semi-crystalline and amorphous characteristics. Thedegradation mechanism of semi-crystalline bioabsorbable polymers ismainly by hydrolysis of ester linkages or other labile bonds orhydrolytically unstable backbone. This is the most prevailing mechanismfor polymer degradation. In general, the degradation occurs in twophases. In the first phase, hydrolysis of amorphous phase occurs andforms low molecular weight water-soluble fragments e.g., lactic acid.This reduction in molecular weight in the amorphous phase does notresult in reduction in mechanical properties as the crystalline regionsprovide the required strength to the structure. Then, hydrolysis ofcrystalline phase occurs which results in loss in molecular weight andmechanical properties. This is followed by enzymatic attack that leadsto metabolism of fragments and results in accelerated polymer mass loss.These fragments then enter the Kreb's Cycle and are excreted as carbondioxide and water. This degradation process can vary from days to monthsto years and it depends on the type of polymer. The factors thataccelerate polymer degradation includes hydrophilic backbone and endgroups, less crystallinity, more porosity and higher surface area, noorientation, no physical aging, low density, presence of additives suchas plasticizers and water soluble or leachable materials.

Additionally, it is well established that the degradation of polymers,such as polylactic acid (PLA) and polyglycolic acid (PGA) are catalyzedby carboxyl end groups formed by chain cleavage and that amorphousregions are preferentially degraded. See Suming Li, “HydroliticDegradation Charcteristics of Aliphatic Polyesters Derived from Lacticand Glycolic Acids”, J Biomed Mater Res (Appl Biomatter) 48: 342-353(1999). In general, the cleavage of an ester bond yields a carboxyl endgroup and a hydroxyl end group wherein the formed carboxyl end groupsare capable of catalyzing hydrolysis of other ester bonds. This processis commonly known as autocatalysis.

One example of fast degradation of PLA polymers is the degradation ofPLA in a phosphate buffer wherein in about a 5-week period ofdegradation, the PLA material becomes heterogeneous with the interior ofthe material being composed of various viscous oligomers. Thisdegradation process is known as “heterogeneous degradation” or “fasterinternal degradation”.

Thus, in an aqueous medium, water penetrates into the polymer materialwhich results in the hydrolytic cleavage of the ester bonds wherein thecleavage of the ester bonds forms a new carboxyl end group therebyaccelerating the reaction of the other ester bonds throughautocatalysis. As part of this process, initially, the degradationoccurs in bulk and is macroscopically homogeneous. However, when solubleoligomers are generated, those oligomers near the surface of the matrixescape from the matrix before being completely degraded whereas thoseoligomers trapped within the matrix results in a higher acidity withinthe polymer matrix than at the surface of the matrix. Thus, theautocatalysis is greater in the bulk (within the matrix) than at thesurface of the matrix and as the degradation of the polymer continuesmore carboxyl end groups are formed inside the matrix leading to anaccelerated internal degradation. Eventually, hollow structures areformed in the material by this degradation phenomenon.

The above-outlined degradation process has been identified for thosepolymers containing PLA and PGA, for example, PLA₇₅GA₂₅; PLA₈₅GA₁₅;PLA_(87.5); PLA₉₆; and PLA₁₀₀.

Bioabsorbable and/or biodegradable polymers consist of bulk and surfaceerodable materials. Surface erosion polymers are typically hydrophobicwith water labile linkages. Hydrolysis tends to occur fast on thesurface of such surface erosion polymers with no water penetration inbulk. The initial strength of such surface erosion polymers tends to below however, and often such surface erosion polymers are not readilyavailable commercially. Nevertheless, examples of surface erosionpolymers include polyanhydrides such as poly (carboxyphenoxyhexane-sebacic acid), poly (fumaric acid-sebacic acid), poly(carboxyphenoxy hexane-sebacic acid), poly (imide-sebacic acid)(50-50),poly (imide-carboxyphenoxy hexane) (33-67), and polyorthoesters(diketene acetal based polymers).

Bulk erosion polymers, on the other hand, are typically hydrophilic withwater labile linkages. Hydrolysis of bulk erosion polymers tends tooccur at more uniform rates across the polymer matrix of the device.Bulk erosion polymers exhibit superior initial strength and are readilyavailable commercially.

Examples of bulk erosion polymers include poly (α-hydroxy esters) suchas poly (lactic acid), poly (glycolic acid), poly (caprolactone), poly(p-dioxanone), poly (trimethylene carbonate), poly (oxaesters), poly(oxaamides), and their co-polymers and blends. Some commercially readilyavailable bulk erosion polymers and their commonly associated medicalapplications include poly (dioxanone) [PDS® suture available fromEthicon, Inc., Somerville, N.J.], poly (glycolide) [Dexon® suturesavailable from United States Surgical Corporation, North Haven, Conn.],poly (lactide)-PLLA [bone repair], poly (lactide/glycolide) [Vicryl®(10/90) and Panacryl® (95/5) sutures available from Ethicon, Inc.,Somerville, N.J.], poly (glycolide/caprolactone (75/25) [Monocryl®sutures available from Ethicon, Inc., Somerville, N.J.], and poly(glycolide/trimethylene carbonate) [Maxon® sutures available from UnitedStates Surgical Corporation, North Haven, Conn.].

Other bulk erosion polymers are tyrosine derived poly amino acid[examples: poly (DTH carbonates), poly (arylates), and poly(imino-carbonates)], phosphorous containing polymers [examples: poly(phosphoesters) and poly (phosphazenes)], poly (ethylene glycol) [PEG]based block co-polymers [PEG-PLA, PEG-poly (propylene glycol), PEG-poly(butylene terephthalate)], poly (α-malic acid), poly (ester amide), andpolyalkanoates [examples: poly (hydroxybutyrate (HB) and poly(hydroxyvalerate) (HV) co-polymers].

Of course, the devices may be made from combinations of surface and bulkerosion polymers in order to achieve desired physical properties and tocontrol the degradation mechanism. For example, two or more polymers maybe blended in order to achieve desired physical properties and devicedegradation rate. Alternately, the device may be made from a bulkerosion polymer that is coated with a surface erosion polymer. The drugdelivery device may be made from a bulk erosion polymer that is coatedwith a drug containing a surface erosion polymer. For example, the drugcoating may be sufficiently thick that high drug loads may be achieved,and the bulk erosion polymer may be made sufficiently thick that themechanical properties of the device are maintained even after all of thedrug has been delivered and the surface eroded. Alternately, the devicecan also be formed from layers of different polymer and drugcombinations to provide programmable drug release during polymerabsorption. Accordingly, in these embodiments according to the presentinvention, the drug 99 (which may include only one or combinations ofdifferent drugs, i.e. more than one type of drug 99) is programmablyreleased from one or both of the first biodegradable and/orbioabsorbable material 75 and the second biodegradable and/orbioabsorbable material 80 as different polymer layers.

Referring now to FIG. 1, the present invention is a biodegradable and/orbioabsorbable medical device, generally designated 50, for placement orimplantation in a patient's body. The medical device 50 is any type ofmedical device, such as a medical implant, and in this example, themedical device 50 is a stent for deployment within a vessel. The medicaldevice 50 has a composite structure of a first biodegradable and/orbioabsorbable material 75 that degrades at a first degradation rate anda second biodegradable and/or bioabsorbable material 80 layered orcoated over or blended with the first biodegradable and/or bioabsorbablematerial 75, wherein the first degradation rate of the firstbiodegradable and/or bioabsorbable material 75 is faster than the seconddegradation rate of the second biodegradable and/or bioabsorbablematerial 80 in accordance with the present invention.

Particularly, the medical device 50 is made of composite structurescomprising different biodegradable and/or bioabsorbable material 75 and80 respectively including coatings or layers or blends of differentbiodegradable and/or bioabsorbable material 75 and 80 respectively. Eachof the biodegradable and/or bioabsorbable materials 75 and 80respectively has a different degradation rate. And, the medical device50 is designed such that the second biodegradable and/or bioabsorbablematerial 80 has a degradation rate that is slower than the degradationrate of the first biodegradable and/or bioabsorbable material 75. And,as will be described in greater detail later in this disclosure, thesecond biodegradable and/or bioabsorbable material 80 is coated orlayered over the first biodegradable and/or bioabsorbable material 75and both first biodegradable and/or bioabsorbable material 75 and secondbiodegradable and/or bioabsorbable material 80 are selected andconfigured or arranged in such a way such that a desired mass loss isachieved to include an accelerated degradation after the medical devicehas achieved its desired functional effect or achieved the end of itsfunctional purpose or useful life. This period of accelerateddegradation occurs after the second biodegradable and/or bioabsorbablematerial 80 coating or layer(s) has degraded thereby exposing portionsof the first biodegradable and/or bioabsorbable material 75. Thus, theperiod of accelerated degradation occurs at a point in time after themedical device 50 has achieved its functional purpose or useful life.

In one embodiment according to the present invention, medical device 50(FIGS. 1-5) is made from composite structures wherein the firststructure (first biodegradable and/or bioabsorbable material 75) servesas a polymer core or polymer backbone and has physical properties andcharacteristics that enable rapid degradation through hydrolysis uponexposure. The second biodegradable and/or bioabsorbable material 80coating or layer(s) over the first structure 75 has physical propertiesand characteristics resulting in a slower degradation rate than thedegradation rate of the first structure 75. One example is to usepoly-L-(lactic acid) (PLLA) on the surface (e.g., as a thick layer orcoating) to serve as the second biodegradable and/or bioabsorbablematerial 80 of the device 50 and poly (glycolic acid) (PGA) as the firstbiodegradable and/or bioabsorbable material 75 to serve as the core orbackbone of the device 50. Both of these materials 75 and 80 providestiffness to the device 50 (in this example, thereby allowing the stent50 to keep a vessel propped open) until the functional effect of thedevice 50 is achieved or the device 50 has reached the end of itsfunctional purpose or useful life. Accordingly, device 50 is designedsuch that as the functional end of the device 50 is being achieved thePLLA material 80 degrades and exposes the PGA material core 75 that, inturn, degrades very rapidly, i.e. at a much greater degradation ratethan the PLLA material coating 80. The absorption of PGA will make thedevice porous and will increase the surface area and will accelerate therate of absorption of any remaining PLLA. This permits the entire device50 to be completely eliminated from the patient's system after thedevice 50 has concluded its functional purpose or useful life. Otherderivatives of PLLA and PGA can be used in addition to other polymers toachieve the desired absorption profile. Examples of other materials for80 include DLPLA; PLA/PGA copolymers (95/5; 85/15); PLA-PCL copolymersthat have lower absorption time than PLLA. Accordingly, appropriateexamples for the second biodegradable and/or bioabsorbable material 80include polylactide based polymers, polyglycolide based polymers, poly(α-hydroxy esters) such as poly (lactic acid), poly (glycolic acid),poly (caprolactone), poly (p-dioxanone), poly (trimethylene carbonate),poly (oxaesters), poly (oxaamides , poly (lactide)-PLLA, poly(lactide/glycolide), poly (glycolide/caprolactone) (75/25), poly(glycolide/trimethylene carbonate), tyrosine derived poly amino acid,poly (DTH carbonates), poly (arylates), poly (imino-carbonates),phosphorous containing polymers, poly (phosphoesters) and poly(phosphazenes), poly (ethylene glycol) based block co-polymers, PEG-PLA,PEG-poly (propylene glycol), PEG-poly (butylene terephthalate), poly(α-malic acid), poly (ester amide), polyalkanoates, poly(hydroxybutyrate (HB), poly (hydroxyvalerate) (HV) co-polymers, DLPLA;PLA/PGA copolymers (95/5; 85/15); PLA-PCL copolymers that have lowerabsorption time than PLLA and their co-polymers and blends.

Examples of other materials for 75 include PGA/PLA (90/10); PGA/PCL(75/25; 50/50; 65/35); poly (p-dioxanone) and their derivatives thathave longer absorption time than PGA. Other examples for 75 include poly(ethylene glycol); citrate esters and other water soluble materials thatwill dissolve and create a higher surface area for faster absorption of80. Accordingly, appropriate examples for the first biodegradable and/orbioabsorbable material 75 include poly (glycolic acid) (PGA), poly(α-hydroxy esters), polyanhydrides such as poly (carboxyphenoxyhexane-sebacic acid), poly (fumaric acid-sebacic acid), poly(carboxyphenoxy hexane-sebacic acid), poly (imide-sebacic acid)(50-50),poly (imide-carboxyphenoxy hexane) (33-67), tyrosine derived poly aminoacid, polyorthoesters (diketene acetal based polymers), phosphorouscontaining polymers, poly (ethylene glycol); citrate esters and otherwater soluble materials that will dissolve and create a higher surfacearea for faster absorption and their co-polymers and blends.

Although medical device 50 is not limited to any particularconfiguration, in certain embodiments according to the presentinvention, medical device 50 has a substantially cylindricalconfiguration and is substantially hollow along its longitudinal axisand terminates at an open end at each end of its cylindricalconfiguration. Accordingly, the configuration of medical device 50 inaccordance with the present invention and as described above is bestsuited as a stent for placement within a vessel for treatment ofcardiovascular disease such as stenosis, artherosclerosis, vulnerableplaque, or ischemic heart disease or as a valve such as a heart valvefor regulating blood flow.

Medical device 50 has structure, features and components 70 thatoptionally include hoops, loops, flexible links or bridges or extensions(not shown) that are either made of a first biodegradable and/orbioabsorbable material 75 which can be in the form of one or more layersor coatings or blends. Additionally, first biodegradable and/orbioabsorbable material 75 is the core which is coated with secondbiodegradable and/or bioabsorbable material 80, i.e. second material 80serves as an initial protective coating for the first biodegradableand/or bioabsorbable material 80 (based on the dramatic differences inthe degradation rates of the materials 75 and 80 respectively).

The first biodegradable and/or bioabsorbable material 75 is used as thebase material for structural aspects 70 of the device 50 such as hoops,loops, flexible links or bridges or extensions of the stent 50 or thehousing, flaps or other components 70 of the desired medical device 50.When applied as a coating 80, the second biodegradable and/orbioabsorbable material 80 is used as the coating material 80 to becoated over and initially protect the structural aspects 75 of thedevice or stent 50 such as hoops, loops, flexible links or bridges orextensions of the stent 50 or the other components of the desiredmedical device 50.

By way of example, the first biodegradable and/or bioabsorbable material75 is a bulk erodible polymer (either a homopolymer, copolymer or blendof polymers) such as any one of the polyesters belonging to the poly(alpha-hydroxy acids) group. This includes aliphatic polyesters suchpoly (lactic acid); poly (glycolic acid); poly (caprolactone); poly(p-dioxanone) and poly (trimethylene carbonate); and their copolymersand blends. Other polymers useful as the first bioabsorbable material 75include amino acid derived polymers [e.g., poly(iminocarbonates)];phosphorous containing polymers [e.g., poly(phosphazenes); poly(phosphoesters)] and poly (ester amide).

The rate of hydrolysis of the first biodegradable and/or bioabsorbablematerial 75 depends on the type of monomer used to prepare the bulkerodible polymer. For example, the absorption times (time to completedegradation or fully degrade) are estimated as follows: poly(caprolactone), poly (trimethylene carbonate) and poly(1-lactic acid)takes about 2-4 years; poly(dioxanone) takes about 7 months; and poly(glycolic acid) takes about 3-6 months. Preferably, the degradation ratefor the first biodegradable and/or bioabsorbable material 75 is between1 day and 3 months.

Absorption rates for copolymers prepared from the monomers such aspoly(lactic acid-co-glycolic acid); poly(glycolic acid-co-caprolactone);and poly(glycolic acid-co-trimethylene carbonate) depend on the molaramounts of the monomers. The degradation of the polymers is byhydrolysis and the byproducts are typically water soluble fragments suchas monomers that are used to prepare the polymers [for example, lacticacid from poly (lactic acid); glycolic acid from poly(glycolic acid)]which are metabolized by enzymatic attack then enters the kreb's cycleand excreted as carbon dioxide and water.

In accordance with the present invention, the second biodegradableand/or bioabsorbable material 80 is having a much slower rate orhydrolysis (degradation rate) than the biodegradable and/orbioabsorbable material 75. For example, based on the hydrolysis ratesoutlined above, PLLA is one appropriate material for the coating 80 andPGA as an appropriate material for the core 75 of the device 50. Forexample, preferably, the degradation rate for the second biodegradableand/or bioabsorbable material 80 is between 3 months and 48 months.

FIG. 3 illustrates a further embodiment of the medical device 50depicted in FIG. 1 wherein the device 50 further includes a drug 99which is incorporated into one or more portions of the device, forexample, drug 99 incorporated into the outer coating layer(s) of thesecond biodegradable and/or bioabsorbable material 80 or within thepolymer core or backbone material 75 (first biodegradable and/orbioabsorbable material 75 which is the basis of the structure,components or features of the of the medical device 50) or drug 99incorporated into both materials 75 and 80 respectively.

Thus, in the example where the medical device 50 is a stent, the device50 depicted in FIG. 3, is a drug-eluting stent wherein drug 99 isreleased from the stent 50 according to a pre-determined drug releaseprofile. Moreover, the degradation or hydrolysis rates of the outermaterial 80 and the inner core 75 are timed to coincide with the desireddrug release profile. Details of an exemplary drug 99 used with thestent 50 as a drug delivery system based on degradation parametersaccording to a desired or pre-determined mass loss curve for the stent50 itself including an accelerated degradation phase after achieving thedesired drug release profile, i.e. after the stent 50 has achieved itsfunctional purpose of delivering its drug 99 into the vessel wall inwhich it is implanted will be described in greater detail later in thisdisclosure. Additionally, one or more drugs 99 can be used in themedical device 50 in accordance with the present invention.

FIG. 4 is a further embodiment of the medical device 50 of FIG. 1wherein the device 50 includes an additive 95 such as a degradationadditive, buffering agent, radiopaque agent or the like for release upondegradation of the material 80 and/or material 75 in accordance with thepresent invention. Additionally, one or more additives 95 can be used inthe medical device 50 in accordance with the present invention. Highlyreactive enzymes, for example such as Proteinase K, are particularlyuseful as degradation additives 95 for use with the medical device 50according to the present invention.

FIG. 5 is a further embodiment of the medical device 50 of FIG. 1wherein the device 50 includes both drug 99 and an additive 95 such as adegradation additive, buffering agent, radiopaque agent or the like forrelease upon degradation of the material 80 and/or material 75 inaccordance with the present invention. Additionally, one or more drugs99 can be used in combination with one of more additives 95 in themedical device 50 in accordance with the present invention.

Additionally, as best illustrated in FIG. 6 and FIG. 7, the presentinvention is also directed to a new and useful medical device 50 that ismade of biodegradable and/or bioabsorbable material 80 which can beeither the main structure 70 of the device 50 and can also be in theform of one or more coatings or blends or layers of the biodegradableand/or bioabsorbable material 80. PLLA is one example polymer that hasbeen identified to be particularly useful as the biodegradable and/orbioabsorbable material 80 for the main structure 70. Additionally,device 50 further includes encapsulated degradation additives 95encapsulated in the biodegradable and/or bioabsorbable material 75 thatupon release (upon hydrolysis of the encapsulating material 75) willpreferentially cleave the polymer backbone material 80. PGA is oneexample polymer that has been identified to be particularly useful asthe biodegradable and/or bioabsorbable material 75 for the mainstructure 70. Examples of the degradation additives 95 are selectedenzymes, high pH materials, etc. One particularly useful enzyme asdegradation additive 95 is proteinase K encapsulated in PGA.

There are several enzymes that can be used for the degradation ofbioabsorbable materials. Enzymatic degradation of polymers depends onthe specificity of enzymes. In vitro degradation studies using enzymesare generally conducted at 37° C. at pH of about 6 to 8.6 in buffer(phosphate or Tris/HCl) in the presence of sodium azide. Proteinase-K,Bromelain and Pronase were amongst the first enzymes that were used todemonstrate enzymatic degradation of PLLA. The enzyme hydrolyses amideand ester bonds. Proteinase-K is very effective and has been used tostudy degradation of PLLA and copolymers. It is a serine proteaseproduced by Tritirachium album, a fungus that grows on native keratin asits sole carbohydrate and nitrogen source. It has been observed thatthis enzyme will preferentially degrade L-lactyl units as opposed toD-lactyl ones, and poly (D-lactide) is not degradable. The enzymedegrades L-L, L-D and D-L bonds as opposed to D-D bond. The degradationpreferentially occurs in the amorphous regions of semi-crystalline PLLA.It cannot degrade the crystalline domains of PLLA and PCL. This is dueto the fact that the active site of Proteinase-K preferentiallyhydrolyses at the disordered chain-packing regions of crystal edgesrather than the chain-folding surfaces of single crystals. Water uptakewill lead to swelling of the polymer and will facilitate enzymaticattack.

Enzymatic degradation of PCL has been investigated in the presence oflipase-type enzymes. These enzymes are capable of cleaving ester bondson hydrophobic surface. Three types of lipase significantly acceleratethe degradation of PCL namely, R. delemer lipase, Rhizopus arrhizuslipase and Pseudomonase lipase. Highly crystalline PCL is totallydegraded in 4 days, therefore these enzymes can degrade amorphous andcrystalline phases of the polymer. These enzymes cannot degrade PLLA.

An Amycolatopsis sp. strain HT-32 has been successfully isolated andused to demonstrate degradation of PLLA. Further isolation of PLLAdegrading microorganisms has led to the isolation of four actinomycetesand four bacteria. One actinomycetes has been identified asAmycolatopsis sp. (strain 41) on the basis of morphological observationsand analysis of 16s RNA. Isolation of PLLA degrading actinomycete istaxonomically similar to the Amycolatopsis strain. Amycolatopsis strainis able to degrade PLLA. 25 reference strains belonging to genusAmycolatopsis, 15 are able to form clear zones on an agar plateemulsified with PLLA. Therefore, Amycolatopsis plays an important rolein the biodegradation of PLLA. Enzyme can be produced from Amycolatopsissp (strain 41) with an estimated molecular weight of about 40 to 42 KDawith an optimum pH and temperature of 6.0 and 37-45° C., respectively,for highest activity. This enzyme will preferentially degrade PLLA butnot poly (ε-caprolactone) and poly(β-hydrobutyrate).

Poly(hydroxybutyrate) [PHB] and its copolymers can be enzymaticallydegraded by extracellular PHB depolymerases isolated from variousenvironments such as Pseudomonas lemoignei, Alcaligenes faecalis,Comamonas testosteroni, Pseudomonas stutzeri, Pseudomonas pickettii andComamonas acidovorans. These enzymes attack preferentially at thedisordered chain packing regions of the crystal edge rather than thechain folding surfaces of the crystalline structure.

Therefore, selection of the enzyme or degradation additive is based onthe type of material that needs to degraded in a short time.

Since the degradation rate of polymer material 75 is greater than thedegradation rate of the polymer core material 80, as soon as theencapsulation material 75 is sufficiently degraded, the degradationadditive 95 is released and acts upon the polymer core material 80thereby increasing the degradation rate of polymer core material 80 inorder to achieve a desired mass loss for the device 50.

Again, for this embodiment as well, additive 95 can be either adegradation additive, buffering agent, radiopaque agent or the like forrelease upon degradation of the encapsulation material 75 in accordancewith the present invention. Additionally, one or more additives 95 canbe used in the medical device 50 in accordance with the presentinvention. Highly reactive enzymes, for example such as Proteinase K,are particularly useful as degradation additives 95 for use with themedical device 50 according to the present invention.

Moreover, as shown in FIGS. 8 and 9 respectively, drug 99 isincorporated into one or more portions of the device 50, for example,drug 99 incorporated directly into the biodegradable and/orbioabsorbable material 80 (which is the basis of the structure,components or features of the of the medical device 50 as shown in FIG.8) or encapsulated together with degradation additive 95 within thebiodegradable and/or bioabsorbable material 75 as shown in FIG. 9.Additionally, drug 99 can be incorporated into both materials 75 and 80respectively.

Thus, in the example where the medical device 50 is a stent, the device50 depicted in FIG. 8 and FIG. 9, is a drug-eluting stent wherein drug99 is released from the stent 50 according to a pre-determined drugrelease profile. Moreover, the degradation or hydrolysis rates of theencapsulation polymer material 75 and ultimately the main structurepolymer material 80 are timed to coincide with the desired drug releaseprofile. Details of an exemplary drug 99 used with the stent 50 as adrug delivery system based on degradation parameters according to adesired or pre-determined mass loss curve for the stent 50 itselfincluding an accelerated degradation phase after achieving the desireddrug release profile, i.e. after the stent 50 has achieved itsfunctional purpose of delivering its drug 99 into the vessel wall inwhich it is implanted will be described in greater detail later in thisdisclosure. Additionally, one or more drugs 99 can be used in themedical device 50 in accordance with the present invention.

Accordingly, for the medical device embodiments of FIGS. 6-9, thebiodegradable and/or bioabsorbable material 80 for the stent structurehas a much slower rate of hydrolysis (degradation rate) that thebiodegradable and/or bioabsorbable material 75 used as the encapsulationmaterial. For example, based on the hydrolysis rates outlined above,PLLA is an appropriate material for the main structure 80 of the device50 and PGA is one appropriate material for the encapsulation material75. Thus, the PGA of the encapsulation material 75 will degrade at amuch faster rate thereby releasing the degradation additive 95, forexample proteinase K, (as well as one or more drugs 99 and other desiredadditives 95, such as buffering agents or radiopaque agents,encapsulated therein) which will enzymatically react with the PLLAstructure material 80 in order to accelerate hydrolysis of the device50.

The encapsulation of the degradation additive 95 or other additives(such as buffering agent or radiopaque agent) can be in the form ofmicroparticles or nanoparticles that do not adversely affect thephysical properties of the device 50.

Different types of buffering agents 95, such as inorganic basic fillers,can be used with all embodiments of the device 50 in accordance with thepresent invention. Some examples of these basic compounds for use asbuffering agents include calcium hydroxyapatite; carbonated apatite;tricalcium phosphate; calcium carbonate; sodium bicarbonate; calciumphosphates; carbonated calcium phosphates; and magnesium hydroxide.Also, acid/based titrating compounds (amine monomers); and lactatedehydrogenase (it will convert lactate in to pyruvate which is the endproduct of glycolysis and starting component of Citric acid cycle) canalso be used as the buffering agent 95.

The inorganic fillers 95 will react with the acid, and neutralize theacid that is formed during the absorption of the polymers 75 and 80. So,they behave as the buffering agents and prevent the acid content in theimmediate environment to be maintained at pH ranging from about 5 toabout 7 and more preferably at pH ranging from about 6 to about 7.4. Thetotal amount of inorganic filler or buffering agent 95 should besufficient to neutralize the total amount of acid that is generatedduring the absorption process. For example, 1 mole of calcium carbonateis needed to react with 2 mol of lactic acid (see below):

CaCO₃(solid)+2CH₃CH(OH)—COOH(aqueous)=>

Ca²⁺(aq)+H₂O+CO₂(aq)+2CH₃CH(OH)—COO-(aq)

A method of formulating the biomaterial structure, materials or coatingsor blends 75 and 80 of the medical device 50 is described in greaterdetail later below. This method is also applicable for combining withdegradation additives 95 (or other additives such as buffering agents orradiopaque agents), and therapeutic agent or drug 99 which can be mixedtogether with the polymer material of the device 50 in some embodimentsor mixed with the biodegradable and/or bioabsorbable material 75 forencapsulating both the degradation additive 95, and optionally togetherwith the drug 99.

Types of appropriate degradation additives 95 include buffers such asbioactive glasses, ceramics and calcium phosphates which are used tostabilize the pH of the environment surrounding the device 50 in orderto control the degradation of the biomaterial structure, materials orcoatings or blends 75 and 80 of the medical device 50. See K. Rezwan etal. “Biodegradable and Bioactive Porous Polymer/Inorganic CompositeScaffolds for Bone Tissue Engineering”, Biomaterials 27 (2006)3413-3431. In general, the basic components of bioactive glasses usefulfor the medical device 50 in accordance with the present invention areSiO₂, NA₂O, CaO and P₂O₅. One particular type of bioactive glass usefulas the degradation additive 95 is 45S5 BIOGLASS® (University of Florida)which is a bioactive glass containing 45% SiO₂, 24.5% NA₂O, 24.4% CaOand 6% P₂O₅ in weight percent.

The use of bioactive glasses as part of the scaffold material of themedical device 50 in order to control degradation of the device 50 is tocontrol a range of chemical properties as well as the rate ofbioresorption upon degradation of the device 50. Thus, the structure andchemistry of the bioactive glasses used in the present invention, suchas sol-gel derived glasses, can be customized at the molecular levelthrough varying such factors as the composition, thermal properties orenvironmental processing history.

Additionally, degradation of the medical device 50 in accordance withthe present invention is also accomplished through adding bioactivephases to the biodegradable and/or bioabsorbable material 75 and 80.Addition of bioactive phases to polymers used in the material 75 and 80alter the polymer degradation behavior, by allowing rapid exchange ofprotons in water for alkali in the glass or ceramic. This mechanism issuggested to provide a pH buffering effect at the polymer surface,thereby modifying the acidic polymer degradation. Inclusion of bioactiveglasses into the medical device 50 can modify surface and bulkproperties of the device 50 itself, including any composite scaffolds,by increasing the hydrophilicity and water absorption of the hydrophobicpolymer matrix, thus altering the degradation kinetics of the device 50.In particular, the inclusion of 45S5 BIOGLASS® particles can increasewater absorption compared to pure polymer foams such as PDLLA and PLGA.It is also known that polymer composites filled with hyaluronic acid(HA) particles hydrolyzed homogeneously due to water penetrating theinterfacial regions of the scaffold.

As described in Rezwan et al., in vitro studies in phosphate-bufferedsaline at 37° C. showed that the addition of bioactive glass, such asBIOGLASS®, increased water absorption and weight loss in comparison topure polymer foams.

Other types of degradation additives 95 are also important for themedical device 50 in accordance with the present invention. For example,either acidic compounds or basic compounds can be incorporated into thepolymeric matrix of the device 50. Incorporation of acidic compounds canaccelerate the degradation of the polymers used in the device 50.Whereas, incorporation of basic compounds can achieve two effectssimultaneously, i.e. base catalysis and neutralization of carboxyl endgroups. Whether the degradation of the device 50 is accelerated orslowed down depends on the relative importance of these effects.

For example, a buffer 95 such as the inorganic compound of coral(containing granules of calcium carbonate) was first used in medicalimplants made of PLA and coral blend matrix in order to slow degradationof the polymer implant in order to facilitate bone tissue regeneration.And, it has been proven that large amounts of coral granules createsinterfaces that facilitate ionic exchanges between the external mediumand the interior of the blend of polymers wherein the carboxyl endgroups were neutralized and the autocatalytic effect eliminated therebyresulting in a blend that was degraded homogeneously.

Another compound known to slow degradation of polymers, which is usefulas a buffer 95 for the medical device 50 of the present invention, iscaffeine. Polymer devices highly loaded with caffeine reduce degradationdue to neutralization of carboxyl end groups while caffeine-free polymerimplants exhibit accelerated degradation due to autocatalysis.

The degradation of polymers, such as PLA and PGA polymers, in thepresence of basic compounds such as those mentioned above depend onparameters such as base catalysis, neutralization of carboxyl endgroups, porosity, device dimensions, load and morphology of incorporatedcompounds.

Other influences on degradation of a polymer implant include molecularweight (MW). Accordingly, the higher the MW of a polymer, the lower thecarboxyl end group concentration, and therefore, the slower thedegradation (at the earlier stages). However, the presence of cyclic oracyclic monomers and oligomers in a polymer matrix can result in a rapiddegradation of the polymer implant.

Moreover, the size and shape of the polymer implant 50 is alsoimportant. For example, very small polymer devices consisting ofmicro-particles, slim fibers or thin films degrade slower than largersized polymer implants because autocatylitic degradation is reduced dueto the easier diffusion of oligomers and neutralization of carboxyl endgroups.

Gamma irradiation, such as through sterilization of medical devices,also has an effect on degradation of a polymer medical device implant.For instance, the gamma irradiation of Dexon® (Davis & Geck) and Vicryl®(Ethicon, Inc.) fibers results in an early pH fall of the degradationmedium and a faster loss of tensile strength.

It will be appreciated by those skilled in the art that the relativeamounts of the biodegradable and/or bioabsorbable material 75 to thebiodegradable and/or bioabsorbable material 80 and relative amounts ofthe degradation additive 95 and/or drug 99 in the composites of thepresent invention will depend upon various parameters including, interalia, the levels of strength, stiffness, and other physical and thermalproperties, absorption and resorption rates, setting and hardeningrates, deliverability, etc., which are required. The desired propertiesof the composites of the embodiments of the present invention and theirlevel of requirement will depend upon the body structure area or anatomywhere the medical device 50 and/or degradation additive 95 (and/orbuffering agent and/or radiopaque agent and/or drug 99) is/are needed.

FIG. 10 is a graph schematically illustrating the different transitionphases of degradation of the physical structure as a function of timefor implantable biodegradable and/or bioabsorbable medical devicesincluding comparisons of the current mass loss curve associated withknown bioabsorbable medical implants versus the desired mass loss curvefor an implantable biodegradable and/or bioabsorbable medical device 50associated with the present invention.

As shown in FIG. 10, the different phases of an implanted biodegradableand/or bioabsorbable device during polymer degradation are physicalstates in which the polymer device exhibits different properties and/orcharacteristics. Additionally, the functional aspects for a givenimplantable bioabsorbable device (e.g., stent as on example for FIG. 10)is limited up to the transition of a device from being “stiff” or in arigid state 100 (Phase I) to being “flexible” or in a flexible state 200(Phase II) to transitioning to a “spongy” form or a spongy state orhighly absorbent state 300 (Phase III) wherein the device loses theretention of physical properties to include transitioning to afragmentation state 400 (Phase IV) whereby the device hydrolyses intofragments that are absorbed by the body. This process for known polymermedical device implants is schematically represented on the “currentmass loss” curve designated by the letter A. Under these circumstances,the prior art polymer devices remain in place in the body until completeabsorption even though it may not be required or desired in the body.This will prevent re-intervention at the site, if needed, and will limittreatment options available to the patients. This may also have afurther inflammatory effect on the tissues associated with the implant,something that is avoided with the accelerated degradation process ordesired mass curve (identified as letter B) of the present invention(medical device 50).

Thus, the degradation profile of the medical device 50 in accordancewith the present invention follows the “desired mass loss” curve B. Inthis way, the medical device 50 is excreted from the body earlier (inless time) than the prior art polymer devices (as shown in curve B).

One example of the medical device 50 in use is for those embodimentswhereby the device 50 is a stent utilizing a drug 99 for elution frompolymer material of the stent (FIGS. 3, 5, 8 and 9) according to thedesired mass loss curve B illustrated in FIG. 10. In this example (forall embodiments using a drug 99), the drug 99 is rapamycin. Rapamycin isa macrocyclic triene antibiotic produced by Streptomyces hygroscopicusas disclosed in U.S. Pat. No. 3,929,992. It has been found thatrapamycin among other things inhibits the proliferation of vascularsmooth muscle cells in vivo. Accordingly, rapamycin may be utilized intreating intimal smooth muscle cell hyperplasia, restenosis, andvascular occlusion in a mammal, particularly following eitherbiologically or mechanically mediated vascular injury, or underconditions that would predispose a mammal to suffering such a vascularinjury. Rapamycin functions to inhibit smooth muscle cell proliferationand does not interfere with the re-endothelialization of the vesselwalls.

Rapamycin reduces vascular hyperplasia by antagonizing smooth muscleproliferation in response to mitogenic signals that are released duringan angioplasty induced injury. Inhibition of growth factor and cytokinemediated smooth muscle proliferation at the late G1 phase of the cellcycle is believed to be the dominant mechanism of action of rapamycin.However, rapamycin is also known to prevent T-cell proliferation anddifferentiation when administered systemically. This is the basis forits immunosuppressive activity and its ability to prevent graftrejection.

As used herein, rapamycin includes rapamycin and all analogs,derivatives and conjugates that bind to FKBP12, and other immunophilinsand possesses the same pharmacologic properties as rapamycin includinginhibition of TOR.

Although the anti-proliferative effects of rapamycin may be achievedthrough systemic use, superior results may be achieved through the localdelivery of the compound. Essentially, rapamycin works in the tissues,which are in proximity to the compound, and has diminished effect as thedistance from the delivery device increases. In order to take advantageof this effect, one would want the rapamycin in direct contact with thelumen walls. Accordingly, in a preferred embodiment, the rapamycin isincorporated onto the surface of the stent or portions thereof.Essentially, the rapamycin is preferably incorporated into the stent 50as described previously above and best illustrated in (FIGS. 3, 5, 8 and9) where the stent 50 makes contact with the lumen wall of the vessel tobe treated.

Rapamycin may be incorporated onto or affixed to the stent 50 in anumber of ways. In exemplary embodiments, the rapamycin is directlyincorporated into a polymeric matrix of the polymer materials 75 and/or80 as described above. The rapamycin elutes from the polymeric matrixover time and enters the surrounding tissue. The rapamycin preferablyremains on the stent for at least one (1) day up to approximately six(6) months, and more preferably between seven (7) days and sixty (60)days (i.e. a period of time ranging between 7 days to 60 days). Thus,these periods of time constitute the functional purpose or functionallife or useful life for the stent 50 for these examples of the presentinvention.

Rapamycin functions to inhibit smooth muscle cell proliferation througha number of mechanisms. In addition, rapamycin reduces the other effectscaused by vascular injury, for example, inflammation. The mechanisms ofaction and various functions of rapamycin are described in detail below.Rapamycin as used throughout this application shall include rapamycin,rapamycin analogs, derivatives and congeners that bind FKBP12 andpossess the same pharmacologic properties as rapamycin, as described indetail below.

Rapamycin reduces vascular hyperplasia by antagonizing smooth muscleproliferation in response to mitogenic signals that are released duringangioplasty. Inhibition of growth factor and cytokine mediated smoothmuscle proliferation at the late G1 phase of the cell cycle is believedto be the dominant mechanism of action of rapamycin. However, rapamycinis also known to prevent T-cell proliferation and differentiation whenadministered systemically. This is the basis for its immunosuppressiveactivity and its ability to prevent graft rejection.

The molecular events that are responsible for the actions of rapamycin,a known anti-proliferative, which acts to reduce the magnitude andduration of neointimal hyperplasia, are still being elucidated. It isknown, however, that rapamycin enters cells and binds to a high-affinitycytosolic protein called FKBP12. The complex of rapamycin and FKPB12 inturn binds to and inhibits a phosphoinositide (Pl)-3 kinase called the“mammalian Target of Rapamycin” or TOR. TOR is a protein kinase thatplays a key role in mediating the downstream signaling events associatedwith mitogenic growth factors and cytokines in smooth muscle cells and Tlymphocytes. These events include phosphorylation of p27,phosphorylation of p70 s6 kinase and phosphorylation of 4BP-1, animportant regulator of protein translation.

It is recognized that rapamycin reduces restenosis by inhibitingneointimal hyperplasia. However, there is evidence that rapamycin mayalso inhibit the other major component of restenosis, namely, negativeremodeling. Remodeling is a process whose mechanism is not clearlyunderstood but which results in shrinkage of the external elastic laminaand reduction in lumenal area over time, generally a period ofapproximately three to six months in humans.

Negative or constrictive vascular remodeling may be quantifiedangiographically as the percent diameter stenosis at the lesion sitewhere there is no stent to obstruct the process. If late lumen loss isabolished in-lesion, it may be inferred that negative remodeling hasbeen inhibited. Another method of determining the degree of remodelinginvolves measuring in-lesion external elastic lamina area usingintravascular ultrasound (IVUS). Intravascular ultrasound is a techniquethat can image the external elastic lamina as well as the vascularlumen. Changes in the external elastic lamina proximal and distal to thestent from the post-procedural timepoint to four-month and twelve-monthfollow-ups are reflective of remodeling changes.

Evidence that rapamycin exerts an effect on remodeling comes from humanimplant studies with rapamycin coated stents showing a very low degreeof restenosis in-lesion as well as in-stent. In-lesion parameters areusually measured approximately five millimeters on either side of thestent i.e. proximal and distal. Since the stent is not present tocontrol remodeling in these zones which are still affected by balloonexpansion, it may be inferred that rapamycin is preventing vascularremodeling.

The data in Table 1 below illustrate that in-lesion percent diameterstenosis remains low in the rapamycin treated groups, even at twelvemonths. Accordingly, these results support the hypothesis that rapamycinreduces remodeling.

Angiographic In-Lesion Percent Diameter Stenosis (%, mean±SD and “n=”)In Patients Who Received a Rapamycin-Coated Stent

TABLE 1.0 Coating Post 4–6 month 12 month Group Placement Follow UpFollow Up Brazil 10.6 ± 5.7 13.6 ± 8.6 22.3 ± 7.2 (15) (30) (30)Netherlands 14.7 ± 8.8 22.4 ± 6.4 —

Additional evidence supporting a reduction in negative remodeling withrapamycin comes from intravascular ultrasound data that was obtainedfrom a first-in-man clinical program as illustrated in Table 2 below.

Matched IVUS data in Patients Who Received a Rapamycin-Coated Stent

TABLE 2.0 4-Month 12-Month Follow-Up Follow-Up IVUS Parameter Post (n =)(n =) (n =) Mean proximal vessel area 16.53 ± 3.53 16.31 ± 4.36 13.96 ±2.26 (mm²) (27) (28) (13) Mean distal vessel area 13.12 ± 3.68 13.53 ±4.17 12.49 ± 3.25 (mm²) (26) (26) (14)

The data illustrated that there is minimal loss of vessel areaproximally or distally which indicates that inhibition of negativeremodeling has occurred in vessels treated with rapamycin-coated stents.

Other than the stent itself, there have been no effective solutions tothe problem of vascular remodeling. Accordingly, rapamycin may representa biological approach to controlling the vascular remodeling phenomenon.

It may be hypothesized that rapamycin acts to reduce negative remodelingin several ways. By specifically blocking the proliferation offibroblasts in the vascular wall in response to injury, rapamycin mayreduce the formation of vascular scar tissue. Rapamycin may also affectthe translation of key proteins involved in collagen formation ormetabolism.

Rapamycin used in this context includes rapamycin and all analogs,derivatives and congeners that bind FKBP12 and possess the samepharmacologic properties as rapamycin.

In a preferred embodiment, the rapamycin is delivered by a localdelivery device to control negative remodeling of an arterial segmentafter balloon angioplasty as a means of reducing or preventingrestenosis. While any delivery device may be utilized, it is preferredthat the delivery device comprises a biodegradable and/or bioabsorbablestent 50 that elutes or releases rapamycin such as those embodimentsillustrated in FIGS. 3, 5, 8 and 9 and described previously above.

Data generated in porcine and rabbit models show that the release ofrapamycin into the vascular wall from drug eluting stents in a range ofdoses (35-430 ug/15-18 mm coronary stent) produces a peak fifty tofifty-five percent reduction in neointimal hyperplasia. This reduction,which is maximal at about twenty-eight to thirty days, is typically notsustained in the range of ninety to one hundred eighty days in theporcine model.

Rapamycin produces an unexpected benefit in humans when delivered from astent by causing a profound reduction in in-stent neointimal hyperplasiathat is sustained for at least one year. The magnitude and duration ofthis benefit in humans is not predicted from animal model data.Rapamycin used in this context includes rapamycin and all analogs,derivatives and congeners that bind FKBP12 and possess the samepharmacologic properties as rapamycin.

As stated above, rapamycin reduces vascular hyperplasia by antagonizingsmooth muscle proliferation in response to mitogenic signals that arereleased during angioplasty injury. Also, it is known that rapamycinprevents T-cell proliferation and differentiation when administeredsystemically. It has also been determined that rapamycin exerts a localinflammatory effect in the vessel wall when administered from a stent inlow doses for a sustained period of time (approximately two to sixweeks). The local anti-inflammatory benefit is profound and unexpected.In combination with the smooth muscle anti-proliferative effect, thisdual mode of action of rapamycin may be responsible for its exceptionalefficacy.

Accordingly, rapamycin delivered from a local device platform, reducesneointimal hyperplasia by a combination of anti-inflammatory and smoothmuscle anti-proliferative effects. Rapamycin used in this context meansrapamycin and all analogs, derivatives and congeners that bind FKBP12and possess the same pharmacologic properties as rapamycin.

Rapamycin has also been found to reduce cytokine levels in vasculartissue when delivered from a stent. Data has shown that rapamycin ishighly effective in reducing monocyte chemotactic protein (MCP-1) levelsin the vascular wall. MCP-1 is an example of aproinflammatory/chemotactic cytokine that is elaborated during vesselinjury. Reduction in MCP-1 illustrates the beneficial effect ofrapamycin in reducing the expression of proinflammatory mediators andcontributing to the anti-inflammatory effect of rapamycin deliveredlocally from a stent. It is recognized that vascular inflammation inresponse to injury is a major contributor to the development ofneointimal hyperplasia.

Since rapamycin may be shown to inhibit local inflammatory events in thevessel it is believed that this could explain the unexpected superiorityof rapamycin in inhibiting neointima.

As set forth above, rapamycin functions on a number of levels to producesuch desired effects as the prevention of T-cell proliferation, theinhibition of negative remodeling, the reduction of inflammation, andthe prevention of smooth muscle cell proliferation. While the exactmechanisms of these functions are not completely known, the mechanismsthat have been identified may be expanded upon.

Studies with rapamycin suggest that the prevention of smooth muscle cellproliferation by blockade of the cell cycle is a valid strategy forreducing neointimal hyperplasia. Dramatic and sustained reductions inlate lumen loss and neointimal plaque volume have been observed inpatients receiving rapamycin delivered locally from a stent. The presentinvention expands upon the mechanism of rapamycin to include additionalapproaches to inhibit the cell cycle and reduce neointimal hyperplasiawithout producing toxicity.

The cell cycle is a tightly controlled biochemical cascade of eventsthat regulate the process of cell replication. When cells are stimulatedby appropriate growth factors, they move from G₀ (quiescence) to the G1phase of the cell cycle. Selective inhibition of the cell cycle in theG1 phase, prior to DNA replication (S phase), may offer therapeuticadvantages of cell preservation and viability while retaininganti-proliferative efficacy when compared to therapeutics that act laterin the cell cycle i.e. at S, G2 or M phase.

Accordingly, the prevention of intimal hyperplasia in blood vessels andother conduit vessels in the body may be achieved using cell cycleinhibitors that act selectively at the G1 phase of the cell cycle. Theseinhibitors of the G1 phase of the cell cycle may be small molecules,peptides, proteins, oligonucleotides or DNA sequences. Morespecifically, these drugs or agents include inhibitors of cyclindependent kinases (cdk's) involved with the progression of the cellcycle through the G1 phase, in particular cdk2 and cdk4.

Examples of drugs 99 that act selectively at the G1 phase of the cellcycle include small molecules such as flavopiridol and its structuralanalogs that have been found to inhibit cell cycle in the late G1 phaseby antagonism of cyclin dependent kinases. Therapeutic agents thatelevate an endogenous kinase inhibitory protein^(kip) called P27,sometimes referred to as P27^(kip1), that selectively inhibits cyclindependent kinases may be utilized. This includes small molecules,peptides and proteins that either block the degradation of P27 orenhance the cellular production of P27, including gene vectors that cantransfact the gene to produce P27. Staurosporin and related smallmolecules that block the cell cycle by inhibiting protein kinases may beutilized. Protein kinase inhibitors, including the class of tyrphostinsthat selectively inhibit protein kinases to antagonize signaltransduction in smooth muscle in response to a broad range of growthfactors such as PDGF and FGF may also be utilized.

As set forth above, the complex of rapamycin and FKPB12 binds to andinhibits a phosphoinositide (PI)-3 kinase called the mammalian Target ofRapamycin or TOR. An antagonist of the catalytic activity of TOR,functioning as either an active site inhibitor or as an allostericmodulator, i.e. an indirect inhibitor that allosterically modulates,would mimic the actions of rapamycin but bypass the requirement forFKBP12. The potential advantages of a direct inhibitor of TOR includebetter tissue penetration and better physical/chemical stability. Inaddition, other potential advantages include greater selectivity andspecificity of action due to the specificity of an antagonist for one ofmultiple isoforms of TOR that may exist in different tissues, and apotentially different spectrum of downstream effects leading to greaterdrug efficacy and/or safety.

In addition, the inhibitor may be formulated for fast-release or slowrelease from the medical device 50 of the present invention with theobjective of maintaining the rapamycin or other drug, agent or compoundin contact with target tissues for a period ranging from three days toeight weeks, i.e. the functional life or useful life for the medicaldevice 50 in this example.

As stated previously, the implantation of a coronary stent inconjunction with balloon angioplasty is highly effective in treatingacute vessel closure and may reduce the risk of restenosis.Intravascular ultrasound studies suggest that coronary stentingeffectively prevents vessel constriction and that most of the lateluminal loss after stent implantation is due to plaque growth, probablyrelated to neointimal hyperplasia. The late luminal loss after coronarystenting is almost two times higher than that observed afterconventional balloon angioplasty. Thus, inasmuch as stents prevent atleast a portion of the restenosis process, the use of drugs, agents orcompounds which prevent inflammation and proliferation, or preventproliferation by multiple mechanisms, combined with a stent may providethe most efficacious treatment for post-angioplasty restenosis.

The polymers selected for the first biodegradable and/or bioabsorbablematerial 75 and the second biodegradable and/or bioabsorbable material80 for some preferred embodiments of the medical device 50 of thepresent invention have been selected based on the properties generallyoutlined below. For example, polyglycolide (PGA), a fast degradingpolymer, has been selected for the biodegradable and/or bioabsorbablematerial 75 for several embodiments of the present invention.

PGA is the simplest linear aliphatic polyester and was used to developthe first totally synthetic absorbable suture, marketed as Dexon in the1960s by Davis and Geck, Inc. (Danbury, Conn.). Glycolide monomer issynthesized from the dimerization of glycolic acid. Ring-openingpolymerization yields high-molecular-weight materials, withapproximately 1-3% residual monomer present. PGA is highly crystalline(45-55%), with a high melting point (220-225° C.) and a glass-transitiontemperature of 35-40° C. Because of its high degree of crystallinity, itis not soluble in most organic solvents; the exceptions are highlyfluorinated organics such as hexafluoroisopropanol. Fibers from PGAexhibit high strength and modulus and are too stiff to be used assutures except in the form of braided material. Sutures of PGA loseabout 50% of their strength after 2 weeks and 100% at 4 weeks, and arecompletely absorbed in 4-6 months. Glycolide has been copolymerized withother monomers to reduce the stiffness of the resulting fibers.

Polylactide (PLA) and poly-L-lactide (PLLA), a slow degrading polymer(when compared to degradation rates associated with PGA), have beenselected for the biodegradable and/or bioabsorbable material 80 forseveral embodiments of the present invention. As known, lactide is thecyclic dimer of lactic acid that exists as two optical isomers, d and1.1-lactide is the naturally occurring isomer, and dl-lactide is thesynthetic blend of d-lactide and l-lactide. The homopolymer of l-lactide(LPLA or PLLA) is a semicrystalline polymer. These types of materialsexhibit high tensile strength and low elongation, and consequently havea high modulus that makes them more suitable for load-bearingapplications such as in orthopedic fixation and sutures.Poly(dl-lactide) (DLPLA) is an amorphous polymer exhibiting a randomdistribution of both isomeric forms of lactic acid, and accordingly isunable to arrange into an organized crystalline structure. This materialhas lower tensile strength, higher elongation, and a much more rapiddegradation time, making it more attractive as a drug delivery system.Poly (l-lactide) (PLLA) is about 37% crystalline, with a melting pointof 175-178° C. and a glass-transition temperature of 60-65° C. Thedegradation time of LPLA (PLLA) is much slower than that of DLPLA,requiring more than 2 years to be completely absorbed. Copolymers ofl-lactide and dl-lactide have been prepared to disrupt the crystallinityof l-lactide and accelerate the degradation process.

Poly(lactide-co-glycolide) [PLGA] copolymers can be formed to extend therange of homopolymer properties. Copolymers of glycolide with bothl-lactide and dl-glycolide have been developed for both device and drugdelivery applications. It is important to note that there is not alinear relationship between the copolymer composition and the mechanicaland degradation properties of the materials. For example, a copolymer of50% glycolide and 50% dl-lactide degrades faster than eitherhomopolymer. Copolymers of l-lactide with 25-70% glycolide are amorphousdue to the disruption of the regularity of the polymer chain by theother monomer. A copolymer of 90% glycolide and 10% l-lactide wasdeveloped by Ethicon as an absorbable suture material under the tradename Vicryl. It absorbs within 3-4 months but has a slightly longerstrength-retention time.

Poly(dioxanone) can be prepared by ring-opening polymerization ofp-dioxanone. This resulted in the first clinically tested monofilamentsynthetic suture, known as PDS (marketed by Ethicon). This material hasapproximately 55% crystallinity, with a glass-transition temperature of−10 to 0° C. The polymer should be processed at the lowest possibletemperature to prevent depolymerization back to monomer. Poly(dioxanone)has demonstrated no acute or toxic effects on implantation. Themonofilament loses 50% of its initial breaking strength after 3 weeksand is absorbed within 6 months, providing an advantage over otherproducts for slow-healing wounds.

Poly (ε-caprolactone) can be prepared by ring-opening polymerization ofε-caprolactone which yields a semicrystalline polymer with a meltingpoint of 59-64° C. and a glass-transition temperature of −60° C. Thepolymer has been regarded as tissue compatible and used as abiodegradable suture in Europe. Because the homopolymer has adegradation time on the order of 2 years, copolymers have beensynthesized to accelerate the rate of bioabsorption. For example,copolymers of ε-caprolactone with dl-lactide have produced materialswith more-rapid degradation rates. A block copolymer of ε-caprolactonewith glycolide, offering reduced stiffness compared with pure PGA, isbeing sold as a monofilament suture by Ethicon, Inc. (Somerville, N.J.),under the trade name Monocryl.

The composites of the present invention can be manufactured in thefollowing process as an example. The preformed polymers, i.e. the firstbiodegradable and/or bioabsorbable material 75 and the secondbiodegradable and/or bioabsorbable material 80 and the degradationadditive 95 (or other additives) and optionally the drug 99 and any ofits required excipients are individually charged into a conventionalmixing vessel having a conventional mixing device mounted therein suchas an impeller i.e. the polymer material 75 and the degradation additive95 and drug 99 (if included) are first mixed forming encapsulateddegradation additive 95 and drug 99 (if included). The biodegradableand/or bioabsorbable material polymer(s) 75 and the degradation additive95 and optionally the drug 99 are mixed at a temperature suitable forthe given polymers as is known in this field until uniformly dispersionis obtained in order to ensure that the degradation additive 95 and drug99 when optionally included as part of the encapsulation by thebiodegradable and/or bioabsorbable polymer 75 (FIGS. 6-9). Then, themixture may be further processed by removing it from the mixing device,cooling to room temperature, grinding, and drying under pressures belowatmospheric at elevated temperatures for a period of time. Typicalencapsulation processes can be used which can include spray drying,coacervation, etc. Alternatively, encapsulation can be prepared byextruding, tray drying, drum drying or the like to form solids which arethen ground to the desired particle size. The encapsulated degradationadditive 95 and drug 99 (if included) is then mixed with thebiodegradable and/or bioabsorbable material 80 using suitabletemperatures and processes steps such as those mentioned above andbelow.

It is important to note that all processing techniques used for thepresent invention will be at sufficient temperatures that will notdegrade the drug 99, the degradation additive 95, the polymer material75 and the polymer material 80.

As mentioned above, articles such as the medical devices 50 themselvesmay be molded from the composites of the present invention by use ofvarious conventional injection and extrusion processes and moldingequipment equipped with dry nitrogen atmospheric chamber(s) atacceptable temperatures.

The composites of this invention can be melt processed by numerousconventional methods to prepare a vast array of useful devices 50. Thesematerials can be injection or compression molded to make implantable,biodegradable and/or bioabsorbable medical and surgical devices,especially biodegradable and/or bioabsorbable vascular devices such asstents including drug eluting stents and biodegradable and/orbioabsorbable cardiovascular devices such as heart valves includingheart valves that are capable of eluting drugs 99.

Alternatively, the composites can be extruded (melt or solution) toprepare fibers and films. The filaments thus produced may be spun asmultifilament yarn, or meshes, knitted or woven, and formed byconventional molding techniques into reinforced devices 50 and utilizedwhere it is desirable that the structure have high tensile strength anddesirable levels of compliance and/or ductility. Useful embodimentsinclude preformed valves or stents for areas where vessels and hearttissue including heart valves are have been or are easily damaged orsurgically removed.

According to the systems and methods of the present invention, a drugdelivery device comprised of polymeric, bioabsorbable materials may bemade by any of a variety of processes. The processes used to prepare thedrug delivery devices are preferably low temperature processes in orderto minimize the degradation of drugs or other bio-active agents that areunstable at high temperatures and are incorporated into the matrix ofbioabsorbable polymeric materials comprising the device. Processingmethods may comprise forming the device from bioabsorbable polymericmaterials via low temperature, solution-based processes using solventsas by, for example, fiber spinning, including dry and wet spinning,electrostatic fiber spinning, co-mingled fibers, solvent extraction,coating, wire-coating, hollow fiber and membrane spinning, spinning disk(thin films with uniform thickness), ink-jet printing (three dimensionalprinting and the like), lyophilization, extrusion and co-extrusion,supercritical fluids, solvent cast films, or solvent cast tubes.Alternately, the drug delivery devices may also be prepared by moreconventional polymer processing methods in melt condition for drugs oragents that are stable at high temperature as by, for example, fiberspinning, extrusion, co-extrusion, injection molding, blow molding,pultrusion and compression molding. Alternately, drugs may also beincorporated in the drug delivery device by diffusion through thepolymer matrix. This may be achieved by several methods such as swellingthe device in a drug-enriched solution followed by high-pressurediffusion or by swelling and diffusing the drug in the device usingsupercritical fluids. Alternately, the drugs or agents may be sprayed,dipped, or coated onto the device after formation thereof from thebioabsorbable polymers. In either case, the polymer matrix, and drug oragent blend when provided, is then converted into a structure such asfibers, films, discs/rings or tubes, for example, that is thereafterfurther manipulated into various geometries or configurations asdesired.

Different processes may provide different structures, geometries orconfigurations to the bioabsorbable polymer being processed. Forexample, tubes processed from rigid polymers tend to be very stiff, butmay be very flexible when processed via electrostatic processing orlyophilization. In the former case, the tubes are solid, whereas in thelatter case, the tubes are porous. Other processes provide additionalgeometries and structures that may include fibers, microfibers, thin andthick films, discs, foams, microspheres and even more intricategeometries or configurations. Melt or solution spun fibers, films andtubes may be further processed into different designs such as tubular,slide and lock, helical or otherwise by braiding and/or laser cutting.The differences in structures, geometries or configurations provided bythe different processes are useful for preparing different drug deliverydevices with desired dimensions, strengths, drug delivery andvisualization characteristics. The fibers, films or tubes may be lasercut to a desired geometry or configuration such as in the shape of astent. Other machining techniques may also be utilized

Different processes may likewise alter the morphological characteristicsof the bioabsorbable polymer being processed. For example, when dilutesolutions of polymers are stirred rapidly, the polymers tend to exhibitpolymer chains that are generally parallel to the overall axis of thestructure. On the other hand, when a polymer solution or melt is shearedand quenched to a thermally stable condition, the polymer chains tend toelongate parallel to the shear direction. Still other morphologicalchanges tend to occur according to other processing techniques. Suchchanges may include, for example, spherulite to fibril transformation,polymorphic crystal formation change, re-orientation of already formedcrystalline lamellae, formation of oriented crystallites, orientation ofamorphous polymer chains, crystallization, and/or combinations thereof.

In the case of a stent comprised of bioabsorbable polymeric materialsformed by supercritical fluids, such as supercritical carbon dioxide,the supercritical fluids are used to lower processing temperaturesduring extrusion, molding or otherwise conventional processingtechniques. Different structures, such as fibers, tubes, films, orfoams, may be formed using the supercritical fluids, whereby the lowertemperature processing that accompanies the supercritical fluids tendsto minimize degradation of the drugs incorporated into the structuresformed.

The bioabsorbable polymer materials comprising the drug delivery deviceaccording to the invention may include radiopaque additives addeddirectly thereto during processing of the matrix of the bioabsorbablepolymer materials to enhance the radiopacity of the device. Theradiopaque additives may include inorganic fillers, such as bariumsulfate, bismuth subcarbonate, bismuth oxides and/or iodine compounds.The radiopaque additives may instead include metal powders such astantalum, tungsten or gold, or metal alloys having gold, platinum,iridium, palladium, rhodium, a combination thereof, or other materialsknown in the art. The particle size of the radiopaque materials mayrange from nanometers to microns, preferably from less than or equal toabout 1 micron to about 5 microns, and the amount of radiopaquematerials may range from 0-99 percent (wt percent).

Because the density of the radiopaque additives is typically very highwhere the radiopaque materials are distributed throughout the matrix ofbioabsorbable materials, dispersion techniques are preferably employedto distribute the radiopaque additives throughout the bioabsorbablematerials as desired. Such techniques include high shear mixing,surfactant and lubricant additions, viscosity control, surfacemodification of the additive, and other particle size, shape anddistribution techniques. In this regard, it is noted that the radiopaquematerials may be either uniformly distributed throughout thebioabsorbable materials of the device, or may be concentrated insections of the device so as to appear as markers similar to asdescribed above.

The amount of drugs or other agents incorporated within the drugdelivery device according to the systems and methods of the presentinvention may range from about 0 to 99 percent (percent weight of thedevice). The drugs or other agents may be incorporated into the devicein different ways. For example, the drugs or other agents may be coatedonto the device after the device has been formed, wherein the coating iscomprised of bioabsorbable polymers into which the drugs or other agentsare incorporated. Alternately, the drugs or other agents may beincorporated into the matrix of bioabsorbable materials comprising thedevice. The drugs or agents incorporated into the matrix ofbioabsorbable polymers may be in an amount the same as, or differentthan, the amount of drugs or agents provided in the coating techniquesdiscussed earlier if desired. These various techniques of incorporatingdrugs or other agents into, or onto, the drug delivery device may alsobe combined to optimize performance of the device, and to help controlthe release of the drugs or other agents from the device.

Where the drug or agent is incorporated into the matrix of bioabsorbablepolymers comprising the device, for example, the drug or agent willrelease by diffusion and during degradation of the device. The amount ofdrug or agent released by diffusion will tend to release for a longerperiod of time than occurs using coating techniques, and may often moreeffectively treat local and diffuse lesions or conditions thereof. Forregional drug or agent delivery such diffusion release of the drugs oragents is effective as well. Polymer compositions and their diffusionand absorption characteristics will control drug elution profile forthese devices. The drug release kinetics will be controlled by drugdiffusion and polymer absorption. Initially, most of the drug will bereleased by diffusion from the device surfaces and bulk and will thengradually transition to drug release due to polymer absorption. Theremay be other factors that will also control drug release. If the polymercomposition is from the same monomer units (e.g., lactide; glycolide),then the diffusion and absorption characteristics will be more uniformcompared to polymers prepared from mixed monomers. Also, if there arelayers of different polymers with different drug in each layer, thenthere will be more controlled release of drug from each layer. There isa possibility of drug present in the device until the polymer fullyabsorbs thus providing drug release throughout the device life cycle.

The drug delivery device according to the systems and methods of thepresent invention preferably retains its mechanical integrity during theactive drug delivery phase of the device. After drug delivery isachieved, the structure of the device ideally disappears as a result ofthe bioabsorption of the materials comprising the device. Thebioabsorbable materials comprising the drug delivery device arepreferably biocompatible with the tissue in which the device isimplanted such that tissue interaction with the device is minimized evenafter the device is deployed within the patient. Minimal inflammation ofthe tissue in which the device is deployed is likewise preferred even asdegradation of the bioabsorbable materials of the device occurs. Inorder to provide multiple drug therapy, enriched or encapsulated drugparticles or capsules may be incorporated in the polymer matrix. Some ofthese actives may provide different therapeutic benefits such asanti-inflammatory, anti-thrombotic; etc.

As described above, polymer stents may contain therapeutic agents as acoating, e.g. a surface modification. Alternatively, the therapeuticagents may be incorporated into the stent structure, e.g. a bulkmodification that may not require a coating. For stents prepared frombiostable and/or bioabsorbable polymers, the coating, if used, could beeither biostable or bioabsorbable. However, as stated above, no coatingmay be necessary because the device itself is fabricated from a deliverydepot. This embodiment offers a number of advantages. For example,higher concentrations of the therapeutic agent or agents may beachievable such as about >50 percent by weight. In addition, with higherconcentrations of therapeutic agent or agents, regional drug delivery(>5 mm) is achievable for greater durations of time. This can treatdifferent lesions such as diffused lesions, bifurcated lesions, smalland tortuous vessels, and vulnerable plaque. These drug-loaded stentscan be delivered by different delivery systems such balloon expandable;self-expandable or balloon assist self-expanding systems.

As mentioned above, the composites of the present invention may also beused to coat substrates, i.e. serve as a biodegradable and/orbioabsorbable polymer coating or a biodegradable and/or bioabsorbabledrug eluting polymer coating, such as biocompatible substrates such asmeshes, the various structural components and elements of medicaldevices, for example, the hoops, loops, flexible links or bridges orextensions of the stent 50 or the housing, flaps or other components ofthe heart valve 50, etc. The coatings or blends 70 would be made byutilizing liquid composites of the present invention which would then beapplied to the substrate by conventional coating techniques such asdipping, spraying, brushing, roller coating, etc.

Additionally, the composites can be molded to form films which areparticularly useful for those applications where a drug delivery matrixin tissue (e.g., growth factors) is desired, for example for achievingangiogenesis and/or myogenesis in cardiovascular tissue including thevessels, myocardium, endocardium and epicardium or pericardium of theheart.

Furthermore, the composites of the present invention can be formed intofoams, with open or closed cells, which are useful for applicationswhere a high rate of tissue ingrowth is required such as remodelingheart tissue for inducing myogenesis or angiogenesis for treatment ofcardiovascular disease such as congestive hear failure (CHF) or ischemicheart disease.

In more detail, the surgical and medical uses of the filaments, films,foams, molded articles, and injectable devices of the present inventioninclude, but are not necessarily limited to vessels or heart tissue. Themedical device 50 in accordance with the present invention can also beused for devices such as clamps, screws, and plates; clips; staples;hooks, buttons, and snaps; preformed tissue substitutes such asprosthetics or grafts, injectable polymers; vertebrae discs; anchoringdevices such as suture anchors; septal occlusion devices; injectabledefect fillers; preformed defect fillers; bone waxes; cartilagereplacements; spinal fixation devices; drug delivery devices; foams withopen or closed cells, and others.

All embodiments of the present invention allow for all of thebiodegradable and/or bioabsorbable material 75 and 80 respectively to beremoved or eliminated from the body in a short period of time after thefunctional aspects of the device 50 have been achieved. Accordingly, thepresent invention allows for re-intervention of the same treatment siteby the doctors to treat the diseased tissue (or organs) in many casesvessels (in the cases where the medical device 50 is a stent). Thus, thepresent invention also permits a programmable drug release of drug 99from the device 50 (FIGS. 3, 5, 8 and 9).

Inasmuch as the foregoing specification comprises preferred embodimentsof the invention, it is understood that variations and modifications maybe made herein, in accordance with the inventive principles disclosed,without departing from the scope of the invention.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes and substitutions will now occur to those skilled inthe art without departing from the invention. Accordingly, it isintended that the invention be limited only by the spirit and scope ofthe appended claims.

1. A medical device comprising: a structure made of one biodegradableand/or bioabsorbable material; a degradation additive encapsulated byanother biodegradable and/or bioabsorbable material forming ananoparticle or microparticle, the nanoparticle or microparticle beingtogether with the one biodegradable and/or bioabsorbable material of thestructure; the other biodegradable and/or bioabsorbable material of thenanoparticle or microparticle having a degradation rate that is fasterthan a degradation rate of the one biodegradable and/or bioabsorbablematerial, the structure experiencing a period of accelerated degradationupon release of the degradation additive from the nanoparticle ormicroparticle.
 2. The medical device according to claim 1, wherein theperiod of accelerated degradation occurs at a point in time after themedical device has achieved a functional purpose.
 3. The medical deviceaccording to claim 2, wherein the degradation rate for the onebiodegradable and/or bioabsorbable material is between 3 months and 48months.
 4. The medical device according to claim 3, wherein thedegradation rate for the other biodegradable and/or bioabsorbablematerial is between 1 day and 3 months.
 5. The medical device accordingto claim 4, wherein the one biodegradable and/or bioabsorbable materialis selected from the group consisting of polylactide based polymers,polyglycolide based polymers, poly (α-hydroxy esters) such as poly(lactic acid), poly (glycolic acid), poly (caprolactone), poly(p-dioxanone), poly (trimethylene carbonate), poly (oxaesters), poly(oxaamides , poly (lactide)-PLLA, poly (lactide/glycolide), poly(glycolide/caprolactone) (75/25), poly (glycolide/trimethylenecarbonate), tyrosine derived poly amino acid, poly (DTH carbonates),poly (arylates), poly (imino-carbonates), phosphorous containingpolymers, poly (phosphoesters) and poly (phosphazenes), poly (ethyleneglycol) based block co-polymers, PEG-PLA, PEG-poly (propylene glycol),PEG-poly (butylene terephthalate), poly (α-malic acid), poly (esteramide), polyalkanoates, poly (hydroxybutyrate (HB), poly(hydroxyvalerate) (HV) co-polymers, DLPLA; PLA/PGA copolymers (95/5;85/15); PLA-PCL copolymers that have lower absorption time than PLLA andtheir co-polymers and blends.
 6. The medical device according to claim5, wherein the other biodegradable and/or bioabsorbable material isselected from the group consisting of poly (glycolic acid) (PGA), poly(α-hydroxy esters), polyanhydrides such as poly (carboxyphenoxyhexane-sebacic acid), poly (fumaric acid-sebacic acid), poly(carboxyphenoxy hexane-sebacic acid), poly (imide-sebacic acid) (50-50),poly (imide-carboxyphenoxy hexane) (33-67), tyrosine derived poly aminoacid, polyorthoesters (diketene acetal based polymers), phosphorouscontaining polymers, PGA/PLA (90/10); PGA/PCL (75/25; 50/50; 65/35);poly (p-dioxanone) and their derivatives that have longer absorptiontime than PGA, poly (ethylene glycol); citrate esters and other watersoluble materials that will dissolve and create a higher surface areafor faster absorption and their co-polymers and blends.
 7. The medicaldevice according to claim 6, further comprising at least one drug. 8.The medical device according to claim 7, wherein the functional purposeof the medical device is for delivering the at least one drug for aperiod of time ranging from at least one (1) day up to approximately six(6) months.
 9. The medical device according to claim 8, wherein thefunctional purpose of the medical device is for delivering the at leastone drug for a period of time ranging from between seven (7) days tosixty (60) days.
 10. The medical device according to claim 9, whereinthe at least one drug is rapamycin.
 11. The medical device according toclaim 4, wherein at least one of the one biodegradable and/orbioabsorbable material and the other biodegradable and/or bioabsorbablematerial have crystalline characteristics.
 12. The medical deviceaccording to claim 4, wherein at least one of the one biodegradableand/or bioabsorbable material and the other biodegradable and/orbioabsorbable material have semi-crystalline characteristics.
 13. Themedical device according to claim 4, wherein at least one of the onebiodegradable and/or bioabsorbable material and the other biodegradableand/or bioabsorbable material have amorphous characteristics.
 14. Themedical device according to claim 4, wherein the one biodegradableand/or bioabsorbable material serves as a polymer core for the medicaldevice.
 15. The medical device according to claim 4, further comprisingat least one additive together with one or both of the one biodegradableand/or bioabsorbable material and the other biodegradable and/orbioabsorbable material.
 16. The medical device according to claim 15,wherein the at least one additive is a degradation additive.
 17. Themedical device according to claim 16, wherein the degradation additiveisselected from the group consisting of Proteinase K, Bromelain,lipase-type enzymes, R. delemer lipase, Rhizopus arrhizus lipase,Pseudomonase lipase, microorganism-type enzymes, Amycolatopsis typeenzymes, and PHB depolymerases.
 18. The medical device according toclaim 17, wherein the at least one additive further comprises abuffering agent selected from the group consisting of bioactive glasses,ceramics, calcium phosphate, inorganic coral, caffeine, inorganic basicfillers, calcium hydroxyapatite, carbonated apatite, tricalciumphosphate, calcium carbonate, sodium bicarbonate, carbonated calciumphosphates, magnesium hydroxide, acid/based titrating compounds, aminemonomers and lactate dehydrogenase.
 19. The medical device according toclaim 18, wherein the at least one additive further comprises aradiopaque agent selected from the group consisting of inorganicfillers, barium sulfate, bismuth subcarbonate, bismuth oxides, iodinecompounds, metal powders, tantalum, tungsten, gold, metal alloys,platinum, iridium, palladium, and rhodium.
 20. The medical deviceaccording to claim 4, wherein the medical device comprises a stent. 21.The medical device according to claim 10, wherein the medical devicecomprises a stent.
 22. The medical device according to claim 7, whereinthe at least one drug is together with the one biodegradable and/orbioabsorbable material.
 22. The medical device according to claim 7,wherein the at least one drug is encapsulated with the degradationadditive in the nanoparticle or microparticle by the other biodegradableand/or bioabsorbable material.
 23. The medical device according to claim7, wherein the at least one drug is programmably released from one orboth of the one biodegradable and/or bioabsorbable material and theother biodegradable and/or bioabsorbable material as different polymerlayers.